The major emphasis of this project was the study of SIV pathogenesis in experimentally- infected macaques, utilizing strains derived from sooty mangabeys (SIVsm) and African green monkeys (SIVagm). SIVsm clones derived from an immunodeficient macaque were employed to study viral factors contributing to the induction of AIDS. A study of SIVsm clones derived from the spleen of an immunodeficient SIV-infected pig-tailed macaque identified a region analogous to the V3 loop of HIV-1 envelope to be responsible for determining tropism. Naturally-occurring variation in this region determined whether viruses infected macaque lymphocytes and/or macrophages and this tropism appeared to be linked to pathogenicity. The degree of variation within the envelope of viruses within tissues of SIV-infected macaques was compared utilizing single stranded conformational poymorphism (SSCP) and sequence analysis. Virus populations within lymphoid tissues were highly heterogeneous whereas, distinct and homogeneous populations were observed in the brain and PBMC. A SIVagm strain (SIVagm9063) was isolated and molecularly cloned after experimental passage through a pig-tailed (PT) macaque. This isolate induced immunodeficiency in experimentally infected pig-tailed macaques but caused an asymptomatic infection of rhesus (RH) macaques and African green monkeys (AGM). An infectious, molecular clone produced a high viral load and reproduced the immunodeficiency syndrome in PT macaques. Probes for in situ hybridization were developed and analysis of tissues of PT macaques, RH macaques and AGM revealed significant diminution in viral load in the latter two species suggesting that disease was directly related to extent of infection. Treatment of SIV infected monkeys with an inhibitor of TNFalpha (pentoxyfilline) failed to alter the course of disease.